Understanding how the widely-abused opiate drugs influence brain function requires a better understanding how the endogenous opioid peptides normally act as neurotransmitters and how their function is altered by chronic opiate abuse. Substantial progress has been made in defining the molecular forms, tissue distribution, specific receptors, and pharmacological actions of the endogenous opioid peptides, yet little is known about their normal physiological role in the mammalian nervous system. We need to know what controls opioid peptide release, where endogenous opioids act, and what physiological effects they normally have. During the past several years, we have been using the rodent hippocampal slice preparation as a model to study the actions of endogenous opioid peptides. The hippocampus has many advantages for this study including a well characterized anatomy and physiology. Two major opioid-containing pathways have been identified in the hippocampus; the molecular forms of the opioid peptides present are known; the distribution of specific opioid receptor binding sites has been defined; and the pharmacological effects of opioids in each of the principal regions of the hippocampus have been characterized. In this study, we will define the effects of endogenously released opioid peptides on the electrophysiological properties of hippocampal neurons. The study is focussed on three specific questions: 1) What are the naloxone-sensitive effects on dentate granule cells following stimulation of opioid-containing perforant path or mossy fibers. 2) What are the direct effects of endogenous opioids on hippocampal interneurons identified by specific cell-surface markers. 3) What are the properties of the ion channels regulated by opioid receptor activation in the opioid-responsive hippocampal neurons. The studies described will examine the electrophysiological actions of endogenous opioid peptides as neurotransmitters in the hippocampus at three levels of resolution. We will study: the role opioid peptides as regulators of synaptic transmission in the neuronal circuit; the direct effects of opioids on identified opioid-responsive interneurons; and the signal transduction mechanisms mediating the opioid effects in acutely isolated opioid-responsive cells. This study will build upon our recent advances in the understanding of opioid action in the hippocampus. We have developed methods that have defined the stimulation conditions required to release the endogenous opioids under physiologically appropriate conditions. We have identified fluorescent cell-surface markers that can be used to label hippocampal interneurons in the hippocampal slice preparation. And we have used whole cell voltage clamp methods on acutely dissociated adult hippocampal neurons to characterize the specific conductances regulated by mu opioid receptor activation in nonpyramidal cells. Information obtained from this study will allow us to construct a detailed description of the role of endogenous opioid peptides in the hippocampal neural network and provide a model of opioid neuropeptide action in normal hippocampal physiology.
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